Budget Impact of Disease-Modifying Treatments and a CRISPR Gene-Edited Therapy for Sickle Cell Disease.

BACKGROUND AND OBJECTIVE: Treatment of sickle cell disease (SCD) has traditionally focused on symptomatic and preventative care. Recent advances in novel therapeutic developments, likely to be orphan-designated, are anticipated to carry a substantial price tag. This study assesses the potential budget impact of adopting disease-modifying treatments, crizanlizumab and voxelotor, and pioneering CRISPR gene-edited therapy, CTX001, in the Belgian healthcare system. METHODS: The perspective of the Belgian healthcare payer (RIZIV-INAMI including patient copayments), a 5-year horizon with a 2-10% uptake of disease-modifying interventions, and a 2% uptake of CTX001 were considered. Data, encompassing target population, current (chronic and acute management, curative hematopoietic stem cell transplantation) and new (crizanlizumab, voxelotor, and CTX001) interventions, clinical effectiveness, adverse events, healthcare resource utilization, and associated costs, were gathered through a comprehensive literature review (first phase) and two Delphi panels involving hematologists (second phase). The cost difference between a "world with and without crizanlizumab, voxelotor, and CTX001" was calculated to obtain the budget impact. Three scenario analyses were conducted: a 5-13% and 4% uptake analysis, a 10-18% and 8% uptake analysis, respectively for disease-modifying treatments (crizanlizumab and voxelotor) and CTX001, and a 0% crizanlizumab uptake and managed entry agreements analysis . A ± 20% univariate sensitivity analysis was performed to test the robustness of the analysis. RESULTS: The total five-year cumulative budget impact was estimated at €30,024,968, with 91% attributed to drug acquisition costs. The largest budget impact share was for CTX001 (€25,575,150), while crizanlizumab (€2,301,095) and voxelotor (€2,148,723) was relatively small. In scenarios one and three, a two-fold increase of the cumulative budget impact to €60,731,772 and a four-fold increase to €120,846,256 from the base case was observed. In scenario three, this budget impact decreased by 63% to €11,212,766. Patient population size, number of treated patients, and drug costs influenced the analysis the most, while discontinuation, acute crisis, and adverse event rates had comparatively minimal impact. CONCLUSIONS: Belgian decision-makers may consider alternative financing models, such as outcome-based risk-sharing agreements or annuities, to ensure sustainable coverage of these treatments. This study adheres to recommended practices for assessing budget impact of orphan drugs, distinguishing it from earlier studies with potentially weaker methodologies.

EU-US data transfers: an enduring challenge for health research collaborations.

EU-US data transfers for health research remain a particularly thorny issue in view of the stringent rules of the EU General Data Protection Regulation (GDPR) and the challenges related to US mass surveillance programs, particularly the manner in which US law enforcement and national security agencies can access personal data originating from the EU. Since the entry into force of the GDPR, evidence of impeded collaborations is increasing, particularly in the case of sharing data with US public institutions. The adoption of a new EU-US adequacy decision in July 2023 does not hold the promise for a long-lasting solution due to the risks of being challenged and invalidated - yet again - at the Court of Justice of the EU. As the research community is calling for answers, the new proposal for a European Health Data Space regulation may hold a key to solving some of the existing issues. In this paper, we critically discuss the current rules and outline a possible way forward for transfers between public bodies.

Patient preferences for inflammatory bowel disease treatments: protocol development of a global preference survey using a discrete choice experiment.

Background: As the therapeutic landscape for inflammatory bowel disease (IBD) continues to expand, a need exists to understand how patients perceive and value different attributes associated with their disease as well as with current and emerging treatments. These insights can inform the development and regulation of effective interventions for IBD, benefiting various stakeholders including healthcare professionals, drug developers, regulators, Health Technology Assessment bodies, payers, and ultimately patients suffering from IBD. In response to this, the present patient preference study was developed with the aim to (1) determine the relative preference weights for IBD treatment and disease related attributes, and (2) explain how preferences may differ across patients with different characteristics (preference heterogeneity). Methods: The patient preference study (PPS) was developed through an 8-step process, with each step being informed by an advisory board. This process included: (1) stated preference method selection, (2) attribute and level development (including a scoping literature review, focus group discussions, and advisory board meetings), (3) choice task construction, (4) sample size estimation, (5) survey implementation, (6) piloting, (7) translation, and (8) pre-testing. The resulting discrete choice experiment (DCE) survey comprises 14 attributes with between two and five varying levels. Participants will answer 15 DCE questions with a partial profile design, where each of the choice questions encompasses two hypothetical treatment profiles showing four attributes. Additionally, questions about patients' socio-demographic and clinical characteristics, as well as contextual factors are implemented. The survey is available in 15 different languages and aims to minimally recruit 700 patients globally. Discussion: This protocol gives valuable insights toward preference researchers and decision-makers on how PPS design can be transparently reported, demonstrating solutions to remaining gaps in preference research. Results of the PPS will provide evidence regarding the disease and treatment related characteristics that are most important for IBD patients, and how these may differ across patients with different characteristics. These findings will yield valuable insights applicable to preference research, drug development, regulatory approval, and reimbursement processes, enabling decision making across the medicinal product life cycle that is aligned with the true needs of IBD patients.

Opportunities and Challenges in Cross-Country Collaboration: Insights from the Beneluxa Initiative.

National pricing and reimbursement agencies face growing challenges with complex health technologies, prompting European policy advancements. Beneluxa is a cross-country collaboration involving Belgium, the Netherlands, Luxemburg, Austria, and Ireland that aims to address sustainable access to medicines. In view of the soon-to-be-implemented EU HTA Regulation, insights and experiences from stakeholders with Beneluxa cross-country collaboration could provide possible transferable learnings. Therefore, this research aims to (i) identify the opportunities and challenges faced by Beneluxa, (ii) gather insights from stakeholders, namely (possible) applicants and policymakers, within and beyond Beneluxa on the initiative and broader cross-country collaboration principles, and (iii) transfer these insights into learnings and recommendations in anticipation of the full implementation of the new HTA Regulation. Fifteen semi-structured interviews were conducted with industry and European HTA/policy stakeholders. The principal challenges discussed by stakeholders encompass hesitancy from the industry toward Beneluxa assessments, which were attributed to procedural and timeline uncertainties, legislative framework ambiguity, and challenges in terms of industry's internal organization. Another challenge highlighted is the resource-intensive nature of the procedure due to diverse approaches among member states. In addition, industry stakeholders mentioned limited communication and procedural complexity. Despite challenges, both stakeholder groups recognized important opportunities for cross-country collaboration. Transferable insights for future cross-country collaboration include transparent communication, clear legislative embedding, internal industry restructuring to facilitate joint HTAs, and member state support for conducting collaborative assessments. The study underscores diverging views among stakeholders on cross-country collaboration's potential to support HTA and the market access of complex health technologies. While acknowledging benefits, there still are challenges, including industry hesitancy, emphasizing the need for transparent communication and clear guidance in the evolving EU HTA landscape.

Heart failure patients' perspectives on treatment outcomes and unmet medical needs: A qualitative preference study.

AIMS: Decision-makers still predominantly focus on the perspective of non-patient stakeholders, which may deviate from the unique perspective of heart failure (HF) patients. To enhance patient-centred decision-making, there is a need for more patient-based evidence derived directly from the patients themselves. Hence, this study aimed to understand (i) HF patients' unmet medical needs and preferred treatment outcomes; (ii) patients' risk tolerance; and (iii) their information needs, uncertainties and satisfaction towards HF treatment. METHODS: This qualitative patient preference study consisted of a literature review with a systematic search strategy and semi-structured interviews with HF patients, analysed using the framework method. During the interviews, patients were asked to rank a predefined list of disease and treatment-related characteristics informed by the literature review and were able to spontaneously raise additional characteristics. RESULTS: The study included 14 Belgian HF patients (age range: 58-79, mean age: 72). (i) Regarding their unmet medical needs, HF patients reported that the most important unmet medical needs were shortness of breath and fatigue, as they negatively impact their quality of life (QoL) and independence. In the ranking exercise, patients prioritized improvements in QoL over improvements in life expectancy, whereby the following characteristics received the highest cumulative score: (1) independence, (2) shortness of breath, (3) impaired renal function, (4) survival, (5) fatigue, (6) risk of hospitalization and (7) communication with and between physicians. Patients most often spontaneously raise characteristics related to the general care process. Mechanism of action, route of administration, dose frequency and weight fluctuations scored among the least important characteristics. (ii) Regarding patients' risk tolerance towards HF treatment, some of the patients expressed zero tolerance for side effects, as they had not yet experienced any discomfort caused by the treatment or disease. (iii) Regarding their information needs, patients voiced their desire to receive practical and comprehensible advice orally from their physician because they highly value individualized treatment decision-making. Patients also expressed uncertainties regarding whether the experienced effects were due to their treatment, disease, ageing or other comorbidities. CONCLUSIONS: This study shows that, besides increasing life expectancy, HF patients prioritize improvements in symptoms and side effects reducing their QoL and independence, such as shortness of breath and fatigue. The patient-relevant characteristics identified in this study, from the perspective of HF patients themselves, may be useful to inform clinical trial endpoint selection and guide downstream drug development, evaluation and clinical decision-making towards addressing the unmet medical needs and treatment outcomes of importance to HF patients.

Implementing the EU HTA regulation: Insights from semi-structured interviews on patient expectations, Belgian and European institutional perspectives, and industry outlooks.

Introduction: The goal of the Health Technology Assessment (HTA) Regulation 2021/2282 is to establish a more harmonized HTA framework, fostering member states cooperation and enabling equal patient access to innovative health technologies in Europe. This research aimed to assess the impact of the regulation on national HTAs, the strategic implications for health technology developers, and its influence on price and reimbursement negotiations. Methods: A scoping literature review encompassing peer-reviewed literature as well as grey literature was conducted. Between February and March 2023, semi-structured interviews (n = 20) were performed with stakeholders from Belgian governmental institutions, European institutions, advanced therapy medicinal product developers, academics, and sickness funds. The interviews were analyzed using the framework analysis method. Results: Numerous steps, such as the development of implementing acts and procedural guidelines remain to be taken. At member state level, national/regional HTA bodies and payers must act to adopt the new concepts of Joint Scientific Consultations (JSC) and Joint Clinical Assessments (JCA) within their national legislation, as well as revise their timelines and prepare for interactions at a European level. Compiling a harmonized PICO (Population, Intervention, Comparator, and Outcome), adapting local procedures, and increasing capacity to actively take part in the JSC and JCA are seen as primary barriers by several stakeholders. Training and education will help HTA bodies, payers, and health technology developers to participate in the European processes. Conclusion: While practical and legal challenges were identified, recommendations (such as actively preparing for the upcoming changes and increasing capacity while providing training) were provided to adapt national and European procedures to the needs of the HTA Regulation 2021/2282. The importance of fostering collaborations and aligning local HTA procedures with the new way of working set out by the Regulation was demonstrated with this study.

An Inclusive Civil Society Dialogue for Successful Implementation of the EU HTA Regulation: Call to Action to Ensure Appropriate Involvement of Stakeholders and Collaborators.

OBJECTIVES: Stakeholder involvement has long been considered a success factor for a joint European health technology assessment (HTA) process, and its relevance is now anchored in the EU HTA Regulation's (EU HTAR) legislative wording. Therefore, we aimed to explore the roles, challenges, and most important activities to increase the level of involvement per stakeholder group. METHODS: At the 2022 Fall Convention of the European Access Academy (EAA), working groups addressed the involvement of patients, clinicians, regulators, health technology developers (HTD), and national HTA bodies and payers within the EU HTA process. Each working group revisited the pre-convention survey results, determined key role characteristics for each stakeholder, and agreed on the most important activities to fulfill the role profile. Finally, the activities suggested per group were prioritized by plenary group. RESULTS: The prioritized actions for patients included training and capacity building, the establishment of a patient involvement committee, and the establishment of a patient unit at the EC secretariat. For clinicians, it included alignment on evidence assessment from a clinical vs. HTA point of view, capacity building, and standardization of processes. The most important actions for regulators are to develop joint regulatory-HTA guidance documents, align processes and interfaces under the regulation, and share discussions on post-licensing evidence generation. HTDs prioritized scientific advice capacity and the review of the scoping process, and further development of the scope of the assessment report fact checks. The top three actions for national HTA bodies and payers included clarification on the early HTD dialogue process, political support and commitment, and clarification on financial support. CONCLUSIONS: Addressing the activities identified as the most important for stakeholders/collaborators in the EU HTA process (e.g., in the implementation of the EU HTA Stakeholder Network and of the guidance documents developed by the EUnetHTA 21 consortium) will be key to starting an "inclusive civil society dialogue", as suggested by the European Commission's Pharmaceutical Strategy.

Can Endangered Biosimilar Markets be Rescued? The Need to Bridge Competing Interests for Long-Term Gain.

Market signals such as: (1) the limited number of biosimilars in the development pipeline, (2) the focus of biosimilar development on high-profit therapeutic areas only, and (3) the increase in the number of biosimilar discontinuations and withdrawals, are indicative of sustainability threats facing biosimilar markets in Europe. Two prominent factors that undermine sustainability are: competing interests between the various stakeholders and a preferential focus on short-term gains, disregarding future sustainability threats, hence the need for effective policies that create sustainable competition in biologic markets. Thus far, measures implemented to foster biosimilar adoption have not been necessarily complied with and have had mixed success. Further, these policies have not consistently led to improving access to affordable biologics. In this commentary, we aim to raise awareness of vulnerabilities of biosimilar markets and of difficulties relating to reaching an agreement on policy solutions with a long-term vision. We propose to build on knowledge from collective action theory to advance in reconciling stakeholder interests. This first-of-its-kind approach can inform long-term solutions for biosimilar markets.

Personalized and longitudinal electronic informed consent in clinical trials: How to move the needle?

Changes in the clinical trials landscape have been driven by advancements in digital technology. The use of electronic informed consent to inform research participants and to obtain their consent electronically has the potential to improve participant-researcher interactions over time, facilitate clinical trial participation, and increase efficiency in clinical trial conduct. A personalized electronic informed consent platform that enables long-term interactions with the research team could function as a tool to empower participant engagement in clinical trials. However, significant challenges persist impeding successful and widespread implementation. This Perspective provides insights into the opportunities and challenges for the implementation of electronic informed consent in clinical trials. It sets out key recommendations to promote the implementation of this innovative approach to the informed consent process, including the creation of uniform electronic informed consent platforms at regional and national level.

Testing and Practical Implementation of a User-Friendly Personalized and Long-Term Electronic Informed Consent Prototype in Clinical Research: Mixed Methods Study.

BACKGROUND: Over the years, there has been increasing interest in electronic informed consent (eIC) in clinical research. The user-friendliness of an eIC application and its acceptance by stakeholders plays a central role in achieving successful implementation. OBJECTIVE: This study aims to identify insights for the design and implementation of a user-friendly, personalized, and long-term eIC application based on a usability study with (potential) research participants and semistructured interviews with stakeholders on the practical integration of such an application into their daily practice. METHODS: An eIC prototype was evaluated and refined through usability testing among Belgian citizens and iterative redesign. On the basis of a digital literacy questionnaire, a heterogeneous sample of participants was established. Participants needed to complete a series of usability tasks related to personalization and long-term interaction with the research team while using the "think aloud" technique. In addition, usability tests involved completing the System Usability Scale questionnaire and taking part in a semistructured feedback interview. Furthermore, semistructured interviews were conducted with ethics committee members, health care professionals, and pharmaceutical industry representatives active in Belgium and involved in clinical research. Thematic analysis was undertaken using the NVivo software (Lumivero). RESULTS: In total, 3 iterations of usability tests were conducted with 10 participants each. Each cycle involved some participants who reported having low digital skills. The System Usability Scale scores related to the tasks on personalization and long-term interaction increased after each iteration and reached 69.5 (SD 8.35) and 71.3 (SD 16.1) out of 100, respectively, which represents above-average usability. Semistructured interviews conducted with health care professionals (n=4), ethics committee members (n=8), and pharmaceutical industry representatives (n=5) identified the need for an eIC system that can be easily set up. For example, a library could be established enabling stakeholders to easily provide background information about a clinical study, presented in the second layer of the interface. In contrast, some functionalities, such as informing participants about new studies through an eIC system, were not considered useful by stakeholders. CONCLUSIONS: This study provides insights for the implementation of a user-friendly personalized and long-term eIC application. The study findings showed that usability testing is key to assessing and increasing the user-friendliness of an eIC application. Although this eIC system has the potential to be usable by a wide audience, participants with low digital literacy may not be able to use it successfully, highlighting the need for additional support for participants or other alternatives to an eIC system. In addition, key lessons emerging from the interviews included ensuring that the application is easy to implement in practice and is interoperable with other established systems.

How can patient preferences be used and communicated in the regulatory evaluation of medicinal products? Findings and recommendations from IMI PREFER and call to action.

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making. Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clincians between October 2016 and May 2022. Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators' understanding of patients' unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions. Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators' experience with PPS implementation and communication in regulatory evaluations.

The impact of policy interventions to promote the uptake of biosimilar medicines in Belgium: a nationwide interrupted time series analysis.

BACKGROUND: The Belgian government has taken several measures to increase the uptake of biosimilars in past years. However, no formal evaluation of the impact of these measures has been made yet. This study aimed to investigate the impact of the implemented measures on biosimilar uptake. METHODS: An interrupted time series analysis was performed using an autoregressive integrated moving average (ARIMA) model with the Box-Jenkins method. All data were expressed as defined daily doses (DDD) per month/quarter and obtained from the Belgian National Institute for Health and Disability Insurance (NIHDI). Three molecules were included in the analysis: etanercept (ambulatory), filgrastim (hospital), and epoetin (hospital). A significance level of 5% was used for all analyses. RESULTS: In the ambulatory care, the effect of a financial prescriber incentive of 2019 was investigated. After this intervention, 44.504 (95% CI -61.61 to -14.812; P < 0.001) fewer etanercept biosimilar DDDs were dispensed monthly than expected in the absence of the intervention. Two interventions were modelled for biosimilars in the hospital setting. The first intervention of 2016 includes prescription targets for biosimilars and monitoring of hospitals on adequate tendering. The second intervention involves an information campaign on biosimilars. After the first intervention, a small decrease in quarterly epoetin biosimilar uptake of 449.820 DDD (95% CI -880.113 to -19.527; P = 0.05) was observed. The second intervention led to a larger increase in quarterly epoetin biosimilar uptake of 2733.692 DDD (95% CI 1648.648-3818.736; P < 0.001). For filgrastim, 1809.833 DDD (95% CI 1354.797-2264.869; P < 0.001) more biosimilars were dispensed immediately after the first intervention and 151.639 DDD (95% CI -203.128 to -100.150; P < 0.001) fewer biosimilars each quarter after the first intervention. An immediate and sustained increase of 700.932 DDD (95% CI 180.536-1221.328; P = 0.016) in quarterly biosimilar volume was observed after the second intervention. All other parameter estimates were not statistically significant. CONCLUSIONS: The results of this study suggest that the impact of past policy interventions to increase the uptake of biosimilars has been variable and limited. A holistic policy framework is required to develop a competitive and sustainable off-patent biologicals market in Belgium.

Balancing benefits and risks in lung cancer therapies: patient preferences for lung cancer treatment alternatives.

Background: In the treatment of Non-Small Cell Lung Cancer (NSCLC) the combination of Immuno- Oncotherapy (IO) and chemotherapy (CT) has been found to be superior to IO or CT alone for patients' survival. Patients and clinicians are confronted with a preference sensitive choice between a more aggressive treatment with a greater negative effect on quality of life versus alternatives that are less effective but have fewer side effects. Objectives: The aims of this study were to: (a) quantify patients' preferences for relevant attributes related to Immuno-Oncotherapy treatment alternatives, and (b) evaluate the maximum acceptable risk (MAR)/Minimum acceptable benefit (MAB) that patients would accept for treatment alternatives. Methods: An online preference survey using discrete-choice experiment (DCE) was completed by NSCLC patients from two hospitals in Italy and Belgium. The survey asked patients' preferences for five patient- relevant treatment attributes. The DCE was developed using a Bayesian D-efficient design. DCE analyses were performed using mixed logit models. Information regarding patient demographics, health literacy, locus of control, and quality of life was also collected. Results: 307 patients (158 Italian, 149 Belgian), stage I to IV, completed the survey. Patients preferred treatments with a higher 5-year survival chance as the most important attribute over all the other attributes. Preference heterogeneity for the attribute weights depended on health literacy, patients' age and locus of control. Patients were willing to accept a substantially increased risks of developing side effects in exchange for the slightest increase (1%) in the chance of surviving at least 5 years from the diagnosis of cancer. Similarly, patients were willing to accept a switch in the mode of administration or complete loss of hair to obtain an increase in survival. Conclusion: In this study, the proportion of respondents who systematically preferred survival over all other treatment attributes was particularly high. Age, objective health literacy and locus of control accounted for heterogeneity in patients' preferences. Evidence on how NSCLC patients trade between survival and other NSCLC attributes can support regulators and other stakeholders on assessing clinical trial evidence and protocols, based on patients' conditions and socio-demographic parameters.

Involvement of the European Medicines Agency in multi-stakeholder regulatory science research projects: experiences of staff members and project coordinators.

Background: The European Medicines Agency (EMA) interacts with many different stakeholders involved in the development of drugs, including academic researchers. In recent years, EMA has collaborated more closely with academia, inter alia by taking part in external research projects such as those set up under the Horizon 2020 program in general and the Innovative Medicines Initiative in particular. The aim of this study was to evaluate the perceived added value of EMA's involvement in these projects, both from the perspective of the Agency's participating Scientific Officers and of the coordinators of the consortia that undertook them. Methods: Semi-structured interviews were conducted with the coordinators of 21 ongoing or recently finalized projects in which EMA has participated, as well as with the Agency experts contributing to them. Results: In total, 40 individuals were interviewed, of whom 23 were project coordinators and 17 were EMA staff members. While most of the projects were reported to suffer from delays due to the SARS-CoV-2 pandemic, the consortia adapted to the circumstances and their members still expected to deliver on their objectives. EMA's input into the projects ranged from providing guidance by reviewing documents and attending meetings to creating project materials and disseminating them. The frequency of communication between EMA and the consortia varied widely. The projects generated a diverse set of outputs, which encompassed new or improved medicinal products, methodological standards, research infrastructures, and educational tools. All of the coordinators expressed that EMA's contributions to their projects had increased the scientific relevance of their consortium's work, and the EMA experts found that the knowledge and the deliverables produced by the projects were valuable, taking into consideration the time they had invested into them. In addition, interviewees highlighted some actions which could be taken to increase the regulatory significance of the project outcomes. Conclusion: EMA's engagement in external research projects benefits the consortia conducting them and supports the Agency's mission to foster scientific excellence and advance regulatory science.

Uncertainty management in regulatory and health technology assessment decision-making on drugs: guidance of the HTAi-DIA Working Group.

OBJECTIVES: Uncertainty is a fundamental component of decision making regarding access to and pricing and reimbursement of drugs. The context-specific interpretation and mitigation of uncertainty remain major challenges for decision makers. Following the 2021 HTAi Global Policy Forum, a cross-sectoral, interdisciplinary HTAi-DIA Working Group (WG) was initiated to develop guidance to support stakeholder deliberation on the systematic identification and mitigation of uncertainties in the regulatory-HTA interface. METHODS: Six online discussions among WG members (Dec 2021-Sep 2022) who examined the output of a scoping review, two literature-based case studies and a survey; application of the initial guidance to a real-world case study; and two international conference panel discussions. RESULTS: The WG identified key concepts, clustered into twelve building blocks that were collectively perceived to define uncertainty: "unavailable," "inaccurate," "conflicting," "not understandable," "random variation," "information," "prediction," "impact," "risk," "relevance," "context," and "judgment." These were converted into a checklist to explain and define whether any issue constitutes a decision-relevant uncertainty. A taxonomy of domains in which uncertainty may exist within the regulatory-HTA interface was developed to facilitate categorization. The real-world case study was used to demonstrate how the guidance may facilitate deliberation between stakeholders and where additional guidance development may be needed. CONCLUSIONS: The systematic approach taken for the identification of uncertainties in this guidance has the potential to facilitate understanding of uncertainty and its management across different stakeholders involved in drug development and evaluation. This can improve consistency and transparency throughout decision processes. To further support uncertainty management, linkage to suitable mitigation strategies is necessary.

Analysis of the characteristics and the degree of pragmatism exhibited by pragmatic-labelled trials of antineoplastic treatments.

BACKGROUND: Pragmatic clinical trials (PCTs) are designed to reflect how an investigational treatment would be applied in clinical practice. As such, unlike their explanatory counterparts, they measure therapeutic effectiveness and are capable of generating high-quality real-world evidence. However, the conduct of PCTs remains extremely rare. The scarcity of such studies has contributed to the emergence of the efficacy-effectiveness gap and has led to calls for launching more of them, including in the field of oncology. This analysis aimed to identify self-labelled pragmatic trials of antineoplastic interventions and to evaluate whether their use of this label was justified. METHODS: We searched PubMed® and Embase® for publications corresponding with studies that investigated antitumor therapies and that were tagged as pragmatic in their titles, abstracts and/or index terms. Subsequently, we consulted all available source documents for the included trials and extracted relevant information from them. The data collected were then used to appraise the degree of pragmatism displayed by the PCTs with the help of the validated PRECIS-2 tool. RESULTS: The literature search returned 803 unique records, of which 46 were retained upon conclusion of the screening process. This ultimately resulted in the identification of 42 distinct trials that carried the 'pragmatic' label. These studies examined eight different categories of neoplasms and were mostly randomized, open-label, multicentric, single-country trials sponsored by non-commercial parties. On a scale of one (very explanatory) to five (very pragmatic), the median PCT had a PRECIS-2 score per domain of 3.13 (interquartile range: 2.57-3.53). The most and least pragmatic studies in the sample had a score of 4.44 and 1.57, respectively. Only a minority of trials were described in sufficient detail to allow them to be graded across all domains of the PRECIS-2 instrument. Many of the studies examined also had features that arguably precluded them from being pragmatic altogether, such as being monocentric or placebo-controlled in nature. CONCLUSION: PCTs of antineoplastic treatments are generally no more pragmatic than they are explanatory.

The role of stakeholder involvement in the evolving EU HTA process: Insights generated through the European Access Academy's multi-stakeholder pre-convention questionnaire.

Involvement of all relevant stakeholders will be of utmost importance for the success of the developing EU HTA harmonization process. A multi-step procedure was applied to develop a survey across stakeholders/collaborators within the EU HTA framework to assess their current level of involvement, determine their suggested future role, identify challenges to contribution, and highlight efficient ways to fulfilling their role. The 'key' stakeholder groups identified and covered by this research included: patients', clinicians', regulatory, and Health Technology Developer representatives. The survey was circulated to a wide expert audience including all relevant stakeholder groups in order to determine self-perception by the 'key' stakeholders regarding involvement in the HTA process (self-rating), and in a second, slightly modified version of the questionnaire, to determine the perception of 'key' stakeholder involvement by HTA bodies, payers, and policymakers (external rating). Predefined analyses were conducted on the submitted responses. Fifty-four responses were received (patients 9; clinicians: 8; regulators: 4; HTDs 14; HTA bodies: 7; Payers: 5; policymakers 3; others 4). The mean self-perceived involvement score was consistently lower for each of the 'key' stakeholder groups than the respective external ratings. Based on the qualitative insights generated in the survey, a RACI Chart (Responsible/Accountable/Consulted/Informed) was developed for each of the stakeholder groups to determine their roles and involvement in the current EU HTA process. Our findings suggest extensive effort and a distinct research agenda are required to ensure adequate involvement of the key stakeholder groups in the evolving EU HTA process.

Biosimilar competition in European markets of TNF-alpha inhibitors: a comparative analysis of pricing, market share and utilization trends.

Background: Factors like the number of biosimilar competitors and competitive pricing strategies from originator companies may influence price competition and biosimilar uptake. Objective: The aim of this study was to analyze multiple facets of biosimilar competition of TNF-alpha inhibitors in Europe by exploring the existence of a biosimilar first-mover advantage, pricing strategies of originator companies, and the evolution in patient access. Methods: Sales and volume data on biosimilar and originator infliximab, etanercept, and adalimumab between 2008 and 2020 were provided by IQVIA. Countries included 24 European Union Member States, Norway, Switzerland, United Kingdom, Serbia, and Bosnia and Herzegovina. Sales value was expressed as ex-manufacturer price per defined daily dose (DDD), and volume data were transformed into the number of DDDs per 1,000 inhabitants per day. Descriptive analyses were conducted based on the evolution in price per DDD, trends in biosimilar and originator market shares and utilization trends. Results: Market entry of the first biosimilars of infliximab and adalimumab resulted in a decrease of the volume-weighted average price (VWAP) per DDD by 13.6% and 0.9% on average, whilst the second biosimilars resulted in a decrease by 26.4% and 27.3%, respectively. The first and second etanercept biosimilars generated a similar decrease in the VWAP per DDD by 9.3% and 9.1% on average, respectively. Average market share captured by the first biosimilars was at least twice as large as the second biosimilars for all molecules. In addition, sharp reductions in price per DDD of Humira® in most countries indicated a pricing strategy resulting in low uptake of adalimumab biosimilars. Lastly, utilization of infliximab, etanercept, and adalimumab following biosimilar entry increased by an average of 88.9%, 14.6%, and 22.4%, respectively. However, introduction of (multiple) biosimilar competitors did not necessarily translate into increase in treatment access for all three molecules across some European countries indicating a shift in utilization from one molecule towards the other(s). Conclusion: Overall, this study revealed that biosimilar entry results in increased utilization and price reduction, although at a heterogenous rate among TNF-alpha inhibitors. Observed trends in market shares indicate a biosimilar first-mover advantage whereas pricing strategies considered to be anti-competitive can limit market uptake.

Patients as research partners in preference studies: learnings from IMI-PREFER.

BACKGROUND: There is growing recognition of the importance of patient and public stakeholder involvement (PPI) in patient preference research. However, limited evidence exists regarding the impact, barriers and enablers of PPI in preference studies. The Innovative Medicines Initiative (IMI)-PREFER project conducted a series of preference case studies which incorporated PPI. OBJECTIVE: To describe: (1) how PPI was operationalized in the PREFER case studies, (2) the impact of PPI, and (3) factors that served to impede and facilitate PPI. METHODS: We reviewed the PREFER final study reports to determine how patient partners were involved. We conducted a thematic framework analysis to characterize the impact of PPI and then administered a questionnaire to the PREFER study leads to identify barriers and facilitators to effective PPI. RESULTS: Eight PREFER case studies involved patients as research partners. Patient partners were involved in activities spanning all phases of the patient preference research process, including in study design, conduct and dissemination. However, the type and degree of patient partner involvement varied considerably. Positive impacts of PPI included improvements in the: (1) quality of the research and research process; (2) patient partner empowerment; (3) study transparency and dissemination of results; (4) research ethics, and (5) trust and respect between the research team and the patient community. Of the 13 barriers identified, the 3 most frequently reported were inadequate resources, insufficient time to fully involve patient partners, and uncertainty regarding how to operationalize the role of 'patient partner. Among the 12 facilitators identified, the two most frequently cited were (1) having a clearly stated purpose for involving patients as research partners; and (2) having multiple patient partners involved in the study. CONCLUSION: PPI had many positive impacts on the PREFER studies. Preference study leads with prior PPI experience reported a greater number of positive impacts than those with no such experience. In light of the numerous barriers identified, multi-faceted implementation strategies should be considered to support adoption, integration and sustainment of PPI within preference research. Additional case studies of patient partner involvement in preference research are needed as well to inform best practices in this area.

Research about patients' preferences for medicinal products and treatments is growing. Such research could be improved if patients were involved as 'research partners,' that is, as active members of the study team itself. To date, however, little is known about the actual experience of involving patients as partners in such research. This paper presents learnings from involving patients as partners in 8 case studies conducted as part of IMI-PREFER, a big, European-based project which aimed to develop recommendations about how to conduct preference research. Involving patients as partners led to improvements in the: (1) quality of the research and research process; (2) recruitment of participants; (3) content and design of patient-facing informational materials; and, (4) how and what study results were shared with patient communities. Our findings showed that it is important to plan for patient partners' involvement early on in the design of the preference study so as to ensure that they are fully integrated into the research team and their opportunity to contribute to all stages of the research is optimized. Such planning should address how patient partners will be paid, what their role responsibilities will include, how and when they will be trained and educated, and how they will be supported throughout the course of the study. Having a clearly stated purpose for involving patients as research partners, selecting patient partners who have had prior research experience and relationships with the researchers, and having multiple patient partners on the study team are all also helpful in supporting successful patient involvement. We need more people to share their experiences with involving patient partners in preference research so that we can continue to improve how this is done.

The application of data altruism in clinical research through empirical and legal analysis lenses.

Background: The legal framework for clinical research in the EU is complex and the lack of harmonization of the relevant legal and ethical rules remains one of the main challenges for stakeholders in the field. The recently adopted Data Governance Act (DGA) and the proposal for a European Health Data Space (EHDS) promise to solve the existing challenges with respect to access to and (re)use of personal data for research, but also risk to further complexify the field. The DGA introduced a novel mechanism - data altruism. Data altruism is understood as the voluntary sharing of personal and non-personal data, based on the consent of data subjects or the permission of natural and legal persons, without seeking a reward and for objectives of general interest. This study aimed to gain insights into the opinion of clinical research stakeholders on data altruism, and to critically discuss key issues pertaining to the application of data altruism from a legal point of view. Methods: Semi-structured interviews with (1) data protection officers (DPOs) and legal experts working with commercial and academic sponsors of clinical trials, (2) investigators, and (3) members of research ethics committees. Data underwent framework analysis. The legal discussion was comprised of legal doctrinal research with focus on the DGA, EHDS proposal, and the interplay with the EU General Data Protection Regulation (GDPR). Results: Fourteen experts took part in the interviews, more than half of which were DPOs/legal experts. Interviewees were based in seven EU Member states and the United Kingdom. The majority of participants were critical towards the data altruism mechanism and pointed out challenges and risks associated with its application. Conclusion: Although data altruism holds the potential to facilitate data sharing, its application in clinical research at the moment is still riddled with uncertainties. The interplay of the DGA rules with the provisions of the GDPR and the EHDS proposal are insufficiently clear and further efforts from the legislator are required to build a working, patient-centered, and research fostering data altruism system.